It has been found that some natural products and organisms are potential sources for chemical molecules having useful biological activity of great diversity. For example, marine sponges have proved to be such a source, and a number of publications have issued disclosing organic compounds derived from marine sponges. Such publications include Scheuer, P. J., Ed. [1978-1983] Marine Natural Products, Chemical and Biological Perspectives, Academic Press, New York; Faulkner, D. [1995] J. Nat. Prod. Rep. 12:223-269; [1994] 11:355-394; [1993] 10:497-539; [1992] 9:323-364; [1991] 8:97-147; [1990] 7:269-309; [1988] 5:613-663; [1987] 4:539-576; [1986] 3:1-33; [1984] 1:551-598; and Uemura, D., K. Takahashi, T. Yamamoto, C. Katayama, J. Tanaka, Y. Okumura, Y. Hirata [1985] J. Am. Chem. Soc. 107:4796-4798.
Indole compounds of marine origin have also been described in Moquin, C., M. Guyot [1984] Tetrahedron Letters 25(44):5047-5048 and Norton, R. S., R. J. Wells [1982] J. Am. Chem. Soc. 104(13):3628-3635.
Utilizing sponges as a source material and supplemented by novel synthetic production methods, new classes of biologically active compounds and new pharmaceutical compositions useful as, for example, antitumor and antiviral agents have been provided to the art. In a specific example, bis-heterocyclic compounds such as bis-indoles have been described as having antimicrobial, antitumor, or antiviral activity. Specifically, the bis-indole compounds known as topsentins are disclosed in U.S. Pat. No. 4,866,084. Dragmacidin and its related compounds isolated from the marine sponge of the Dragmacidon sp. are disclosed in U.S. Pat. No. 4,895,844. Similarly, the nortopsentins have been disclosed in U.S. Pat. No. 4,970,226. These patents are herein incorporated by reference. These compounds, as well as the homocarbonyltopsentins and hamacanthins, have also been described as having inhibitory activity against cellular inflammatory responses. See U.S. Pat. Nos. 5,290,777 and 5,464,835 which are also hereby incorporated by reference. Marine derived imidazole compounds have been described in the literature (Tsujii, S., K. L. Rinehart, S. P. Gunasekera, Y. Kashman, S. S. Cross, M. S. Lui, S. A. Pomponi, M. C. Diaz [19881] J. Org. Chem.53:5446-5453; Sakemi, S. H. H. Sun [1991] J. Org. Chem. 56:4304-4307; Wright, A. E., S. A. Pomponi, S. S. Cross, P. McCarthy [1992] J. Org. Chem. 57:4772-4775). Marine derived indole compounds have also been described in the literature (Kohmoto, S., Y. Kashman, O. J. McConnell, K. L. Rinehart, A. E. Wright, F. Koehn [1988] J. Org. Chem. 53:3116-3118; Gunasekera, S. P., P. J. McCarthy, M. Kelly-Borges [1994] J. Nat. Prod. 10:1437-1441). The present invention provides a novel utility for these and related compounds, namely as inhibitors of neural nitric oxide production.
Since the discovery of its role in regulating vascular smooth muscle tone in the mid-1980's, the understanding of the physiologic and pathologic roles of nitric oxide (NO) has expanded significantly. The endogenous production of NO from the metabolism of L-arginine occurs by three well characterizednitric oxide synthase (NOS) enzymes: endothelial constitutive NOS (ecNOS), inducible NOS (iNOS) and brain or neural-derived NOS (bNOS or nNOS). This variety of NOS isoforms reflects the diverse range of activities attributed to NO. These activities include the regulation of blood pressure, gastric motility, anti-bacterial activity, and neurotransmission (Fukuto, J. M., G. Chaudhuri [1995] Annu. Rev. Pharmacol. Toxicol. 35:165-194; Yun, H. Y., V. L. Dawson, T. M. Dawson [1996] Crit. Rev. Neurobiol. 10:291-316; Molina, J. A., F. J. Jimenez-Jimenez, M. Orti-Pareja, J. A. Navarro [1998] Drugs Aging 12:251-259). The highly reactive and cytotoxic nature of NO is also suspected in several neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's diseases (Molina, J. A., F. J. Jimenez-Jimenez, M. Orti-Pareja, J. A. Navarro [1998] Drugs Aging 12:251-259; Thorns, V., L. Hansen, E. Masliah [1998] Exp. Neurol 150:14-20). In addition, evidence from many lines of research indicate that brain inflammation contributes to the pathogenesis of Alzheimer's disease and that secretory products of activated glial cells, such as nitric oxide, mediate this inflammatory process (Gahtan, E. and J. B. Overmier [1999] Neurosci: Biobehav. Rev. 23:615-533; Hays, S. J. [1988] Curr. Pharm. Ds. 4(4):335-348; McCann, S. M. [1997] Exp. Gerontol. 32:431-440; McCann, S. M., J. Licinio, M. L. Wong, W. H. Yu, S. Karanth, and V. Rettorri [1998] Exp. Gerontol. 33(7-8):813-826. Inflammatory diseases, such as arthritis, owe their destructive properties to the over-production of nitric oxide by iNOS which is found in the synovial tissue and cartilage of affected arthritic joints (Amin, A. R., M. Attur, and S. B. Abramson [1999] Curr. Opin. Rheumatol. 11(3):202-209). Finally, evidence suggests the role of nitric oxide in the pathogenesis of asthma. High levels of exhaled nitric oxide are present in the exhalant of adult and pediatric patients, suggesting over-production of nitric oxide as a consequence of the inflammatory process (Baraldi, E., C. Dario, R. Ongaro, M. Scollo, N. M. Azzolin, N. Panza, N. Paganini, and F. Zacchello [1999] Am. J. Respir. Crit. Care Med. 159(4 Pt. 1):1284-1288; Sanders, S. P. [1999] Proc. Soc. Exp. Biol. Med. 220(3):123-132; Stirling, R. G., S. A. Kharitonov, D. Campbell, D. S. Robinsin, S. R. Durham, K. F. Chung, P. J. Barnes [1998] Thorax 53(12):1030-1034). Therefore bNOS and iNOS are viable targets for the development of new therapeutic antagonists. Previous studies have shown that some imidazole unit containing compounds are able to inhibit bNOS (Fukuto, J. M., G. Chaudhuri [1995] Annu. Rev. Pharmacol. Toxicol. 35:165-194; Yun, H. Y., V. L. Dawson, T. M. Dawson [1996] Crit. Rev. Neurobiol. 10:291-316; Molina, J. A., F. J. Jimenez-Jimenez, M. Orti-Pareja, J. A. Navarro [1998] Drugs Aging 12:251-259; Thorns, V., L. Hansen, E. Masliah [1998] Exp. Neutrol 150:14-20; Handy, R. L. C., H. L. Harb, P. Wallace, Z. Gaffen, K. J. Whitehead, P. K. Moore [1996] Brit. J. Pharmacol. 119:423-431).
The advantages and scope of applicability of the present invention will become apparent from the detailed descriptions given herein; it should be understood, however, that the detailed descriptions, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent from such descriptions.